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Original Investigation |

Potential Role of In Vivo Confocal Microscopy for Imaging Corneal Nerves in Transthyretin Familial Amyloid Polyneuropathy

Antoine Rousseau, MD1; Cecile Cauquil, MD2; Benedicte Dupas, CO3,4,5; Antoine Labbé, MD, PhD3,4,5; Christophe Baudouin, MD, PhD3,4,5; Emmanuel Barreau, MD1; Marie Théaudin, MD, PhD2; Catherine Lacroix, MD2,6; Anne Guiochon-Mantel, MD, PhD7; Anouar Benmalek, PhD8; Marc Labetoulle, MD, PhD1; David Adams, MD, PhD2
[+] Author Affiliations
1Department of Ophthalmology, Bicêtre Hospital, Assistance Publique–Hôpitaux de Paris, Département Hospitalo-Universitaire Vision and Handicaps, Paris-Sud University, French Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, Le Kremlin-Bicêtre, France
2Department of Neurology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Sud University, Institut pour la Recherche Médicale U 1195, French Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, Le Kremlin-Bicêtre, France
3Department of Ophthalmology, Quinze-Vingts National Eye Center, Paris, France
4Department of Ophthalmology, Ambroise Paré Hospital, Assistance Publique–Hôpitaux de Paris, Département Hospitalo-Universitaire Vision and Handicaps, Boulogne-Billancourt, France
5Department of Ophthalmology, Versailles Saint-Quentin-en-Yvelines University, Versailles, France
6Department of Pathology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Sud University, French Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, Le Kremlin-Bicêtre, France
7Department of Molecular Genetics, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Sud University, French Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, Le Kremlin-Bicêtre, France
8Department of Biomathematics, Faculty of Pharmacy, Paris-Sud University, Chatenay-Malabry, France
JAMA Ophthalmol. 2016;134(9):983-989. doi:10.1001/jamaophthalmol.2016.1889.
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Importance  Small fiber neuropathy (SFN) is an important feature of transthyretin familial amyloid polyneuropathy (TTR-FAP). A practical and objective method for the clinical evaluation of SFN is needed to improve the management of this disease. In vivo confocal microscopy (IVCM) of the corneal nerves, a rapid noninvasive technique, may be used as a surrogate marker of SFN.

Objective  To determine the correlation of SFN with IVCM in patients with TTR-FAP.

Design, Setting, and Participants  A prospective, single-center, cross-sectional controlled study was conducted at the French National Reference Center for TTR-FAP from June 1, 2013, to June 30, 2014. Fifteen patients with TTR-FAP underwent a complete neurologic examination, including Neuropathy Impairment Score of the Lower Limbs, hand grip strength, and evaluation of vegetative dysfunction, as well as electrophysiologic studies (nerve conduction and electrochemical skin conductance) and intraepidermal nerve fiber density quantification. Patients and 15 controls (matched for age and sex) underwent ophthalmologic assessments, including corneal esthesiometry and IVCM.

Main Outcomes and Measures  Correlation of corneal nerve fiber length (CNFL) with the severity of SFN.

Results  Of the 15 patients enrolled in the study, 6 were women (40%); mean (SD) age was 54.4 [13.7] years. The CNFL was shorter in the patients than in controls (13.08 vs 17.57 mm/mm2; difference of 4.49 [95% CI, 0.72 to 8.27]; P = .02). The patients’ CNFL correlated with the severity of both autonomic neuropathy assessed by the Compound Autonomic Dysfunction Test (rs = 0.66 [95% CI, 0.22 to 0.87]; P = .008) or electrochemical skin conductance (rs = 0.80 [95% CI, 0.50 to 0.93]; P < .001) and sensorimotor neuropathy assessed using the Neuropathy Impairment Score of the Lower Limbs (rs = −0.58 [95% CI, −0.84 to −0.11]; P = .02). Patients with altered sensory nerve action potentials and intraepidermal nerve fiber density had a shorter CNFL (P = .04 and P = .02, respectively). The CNFL could be measured in all patients compared with sensory nerve action potentials (11 patients [73%; 95% CI, 44% to 92%]; P < .001) and intraepidermal nerve fiber density (4 patients [27%; 95% CI, 8% to 55%]; P < .001).

Conclusions and Relevance  In these 15 patients with TTR-FAP, IVCM measurement permitted rapid, noninvasive evaluation of small-fiber alterations in patients and could be used to assess SFN in this setting. The CNFL could be measured in all patients, thus avoiding the floor effect seen with other neuropathy measures. Longitudinal studies with more cases evaluated are needed to define the place of IVCM in monitoring patients with TTR-FAP.

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Figure 1.
Tracing and Quantification of Subbasal Corneal Nerve Fibers Using NeuronJ Software

A, In vivo confocal microscopy (IVCM) image of subbasal corneal nerves in a control participant. B, After tracing the nerve, NeuronJ software (National Institutes of Health, http://www.imagescience.org/meijering/software/neuronj/) quantifies the length of the traced nerves and provides corneal nerve fiber length in millimeters per millimeters squared.

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Figure 2.
Intraepidermal Nerve Fibers and Subbasal Corneal Nerves

Moderately affected individual (patient 5) with lower-limb skin biopsy (LLSB) indirect immunofluorescence: arrowheads indicate intraepidermal nerve fibers (IENFs) (A), and in vivo confocal microscopy (IVCM) shows diminished innervation (B). Severely affected individual (patient 3) with LLSB indirect immunofluorescence showing no IENF (C) and IVCM indicating scarce corneal nerves.

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Figure 3.
Correlation Between Neurologic Findings and Corneal Nerve Fiber Length (CNFL)

CADT indicates Compound Autonomic Dysfunction Test; ESC, electrochemical skin conductance, NIS-LL, Neuropathy Impairment Score of the Lower Limbs; ONLS, Overall Neuropathy Limitations Scale; and PND, Polyneuropathy Disability Scale. Bullets indicate individual patients’ values; solid lines, statistical significance; dashed line, statistical nonsignificance.

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